The present invention relates to a new use of the known drugs, clonidine and lofexidine.
Clonidine, 2-(2,6-dichloroanilino)-2-imidazoline, is a widely investigated drug which is a potent antihypertensive agent, commercially available, e.g., as Catapres.RTM. (Boehringer Ingelheim). It has also been found to alleviate migraine headache (Brogden et al, Drugs 10: 357-365, 1975), premenstrual tension (Ylikorkala. Ann. Chir. Gynaecol. Fenn. 64: 242-245, 1975) and symptoms associated with alcohol withdrawal such as tremors, sweating and anxiety (Bjorkqvist, Acta Psychiat. Scan. 52: 256-263, 1975). More recently clonidine has been reported to produce analgesia (Fielding et al, J. Pharmacol. Exp. Ther. 207: 899-905, 1978), to reduce an anxiety-related behavior (Bullock et al, Pharmacologist 20: 223, 1978), and to alleviate symptoms of narcotic withdrawal in experimental animals (Fielding et al supra and Meyer et al, Pharmacologist 18: 236, 1976) and human patients (Gold et al, Lancet 2: 929-930, 1978 and Washton et al, ACNP Abstracts, 1978). It is also known as a pilomotor agent (U.S. Patent 3,190,802 and a vasoconstrictor (U.S. Pat. No. 3,202,660). It has further been reported to inhibit intestinal cholinergic activity through stimulation of alpha- 2-adrenergic receptors (Drew, Proc. Brit. Pharmacol. Soc. 57P: 513, 1977).
Lofexidine, 2-[.alpha.-(2,6-dichlorophenoxy)ethyl]-.DELTA..sup.2 -imidazoline, is an experimental compound structurally related to clonidine. Like clonidine, lofexidine has antihypertensive activity in laboratory animals and man (Burke et al, Clin. Pharmacol. Therap. 21: 99-100, 1977). Furthermore, lofexidine was recently found to block morphine withdrawal signs in addicted rats (Shearman et al, Submitted for publication to Pharmacol. Biochem. Behav.).
Among the symptoms alleviated by these two compounds in the foregoing uses in diarrhea. For example, Meyer et al supra reported that clonidine blocked naloxone-induced diarrhea in narcotic dependent rats. Similar observations have been made by Shearman et al supra, who found clonidine to be about four times as potent as lofexidine in this regard. Clonidine has also been disclosed to reduce defecation induced by emotionality in the rat (Laverty et al, Brit. J. Pharmacol. 35: 253-264, 1969).
In these cases, the two compounds were not employed or reported as antidiarrheal agents per se. Rather, they were found to alleviate diarrhea which was a symptom of an underlying neurogenic effect being investigated with the compound. That is, in the prior art, the alleviated diarrhea was induced by central nervous system disorders.
Among the reported side effects of clonidine treatment for hypertension is constipation (P.D.R., 33rd Ed., Baker (1979), p. 558), a common side effect for very many drugs. Inducement of constipation does not establish or indicate antidiarrheal activity.